The E2F Pathway Score as a Predictive Biomarker of Response to Neoadjuvant Therapy in ER+/HER2− Breast Cancer

Abstract

<jats:p>E2F transcription factors play critical roles in the cell cycle. Therefore, their activity is expected to reflect tumor aggressiveness and responsiveness to therapy. We scored 3905 tumors of nine breast cancer cohorts for this activity based on their gene expression for the Hallmark E2F targets gene set. As expected, tumors with a high score had an increased expression of cell proliferation-related genes. A high score was significantly associated with shorter patient survival, greater MKI67 expression, histological grade, stage, and genomic aberrations. Furthermore, metastatic tumors had higher E2F scores than the primary tumors from which they arose. Although tumors with a high score had greater infiltration by both pro- and anti-cancerous immune cells, they had an increased expression of immune checkpoint genes. Estrogen receptor (ER)-positive/human epidermal growth factor receptor 2 (HER2)-negative cancer with a high E2F score achieved a significantly higher pathological complete response (pCR) rate to neoadjuvant chemotherapy. The E2F score was significantly associated with the expression of cyclin-dependent kinase (CDK)-related genes and strongly correlated with sensitivity to CDK inhibition in cell lines. In conclusion, the E2F score is a marker of breast cancer aggressiveness and predicts the responsiveness of ER-positive/HER2-negative patients to neoadjuvant chemotherapy and possibly to CDK and immune checkpoint inhibitors.</jats:p>

High G2M Pathway Score Pancreatic Cancer is Associated with Worse Survival, Particularly after Margin-Positive (R1 or R2) Resection

“…Tumor immune microenvironment has been repeatedly demonstrated to be deeply involved in cancer progression by our group and others [ 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 ]. Recently, antitumor immunity was reported to correlate with increased cell cycle activity in pancreatic cancer [ 41 , 42 ].…”

“…The average value was used for genes with multiple probes. Gene expression data, which were transformed for log 2 , were used in all analyses as we have previously reported [ 6 , 17 , 36 , 58 , 66 ]. We used published data of Hussain et al (GSE62452; tumor sample; n = 69, adjusted pancreases sample; n = 61) [ 67 ], Chen et al (GSE57495; n = 63) [ 68 ], and Bocklandt et al (GSE28746; tumor sample; n = 45, adjusted pancreases sample; n = 45) [ 69 ] to investigate the association of the G2M pathway scores with patient survival.…”

“…The xCell algorithm was used to estimate tumor-infiltrating immune cells in bulk tumors. Data was downloaded through the xCell website ( ), as we previously reported [ 6 , 17 , 36 , 66 ].…”

ITPKC as a Prognostic and Predictive Biomarker of Neoadjuvant Chemotherapy for Triple Negative Breast Cancer

“…It is well known that highly proliferative cancers are more likely to respond to cytotoxic chemotherapy [ 9 , 10 , 39 , 40 ]. Given our results that low- ITPKC expression TNBCs are highly proliferative, we hypothesized that they are associated with better NAC response.…”

“…TNBC is known to relate to several proliferation-related pathways [ 7 , 8 ]. Our group has previously reported that TNBC has high activity of the E2F pathway [ 9 ] and G2M checkpoint pathway [ 10 ], both of which are essential components of the cell cycle and critical for cell proliferation.…”