Abstract PS4-35: The E2F cell cycle pathway score to predict treatment response among patients with breast cancer

Abstract

Abstract Cell cycle progression is a critical component of cell proliferation, and continuous proliferation is one of the hallmarks of cancer. Components regulating the E2F pathway have been identified in nearly every human malignancy and many of them including E2F transcription factors themselves play major roles in cancer progression, metastasis and treatment response of breasts cancer. Their activity therefore is expected to reflect tumor aggressiveness and responsiveness to therapy. We scored 3,905 tumors of nine breast cancer cohorts for this activity based on their 200 gene expression for the Hallmark E2F targets gene set. As expected, tumors with a high score had increased expression of cell proliferation-related genes, including G2M checkpoint, MYC targets v1 and v2, MITOTIC spindle, MTORC1 signaling, UNFOLDED protein response, and DNA repair in both the TCGA and METABRIC cohorts (false discovery rate < 0.001 in both cohorts). A high score was significantly associated with greater MKI67 expression (p < 0.001 in both cohorts), histological grade (p < 0.001 in both cohorts), and AJCC pathological stage (p < 0.001 in both cohorts). And Indel and single nucleotide variation neoantigen loads were associated with a high E2F pathway score (p = 0.006 and 0.047 respectively). Furthermore, the E2F pathway score correlated positively with copy number alteration (Spearman r = 0.55, p < 0.001). Intra-tumoral genome heterogeneity and proliferation score were significantly associated with the E2F pathway score as well (p < 0.001). The high E2F pathway score group demonstrated significantly higher fractions of not only pro-cancerous regulatory T cells, helper T cell (Th2), but also anti-cancerous CD4 memory T cell, helper T cell (Th1), and M1 macrophage as well as B cells compared to the low score group in the TCGA cohort (p < 0.001). Similar trends were observed in the METABRIC cohort. Furthermore, metastatic tumors had higher E2F scores than the primary tumors from which they arose especially luminal and normal subtype (p = 0.006 and p < 0.001). Interestingly, metastases with a high E2F score were associated with significantly worse PFS in the whole cohort, as well as patient sub-groups with local recurrence and with liver metastasis (p = 0.018, p = 0.025 and p = 0.027). Additionally, the E2F pathway score was significantly decreased with good response to chemotherapy (p < 0.001) and demonstrated higher pCR rate after neoadjuvant therapies in the high E2F pathway score group of estrogen receptor (ER)-positive/HER2-negative cancer (p < 0.001). The E2F score was significantly associated with expression of cyclin-dependent kinase (CDK)-related genes, including CCNE1, CDKN2A, CDKN2D, CDK2, CDK4 and CDK6 (all p < 0.001), and immune checkpoint molecule-related genes including PD-L1/2, CTLA4, IDO1, LAG3 and TIGIT (p = 0.013, 0.014, < 0.001, < 0.001, < 0.001 and 0.002, respectively). These results were validated by other cohort. Finally, the E2F score was strongly correlated with sensitivity to CDK inhibition in ER+/HER2- breast cancer cell-lines (Spearman r = 0.90, p = 0.04). In conclusion, the E2F score is a marker of breast cancer aggressiveness and predicts responsiveness of ER+/HER2- patients to neoadjuvant chemotherapy and possibly to CDK and immune checkpoint inhibitors. Citation Format: Masanori Oshi, Hideo Takahashi, Yoshihisa Tokumaru, Ryusei Matsuyama, Itaru Endo, Kazuaki Takabe. The E2F cell cycle pathway score to predict treatment response among patients with breast cancer [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS4-35.