Discussion
tumor, neutropenia, T-cell infiltration, mTNBC, chemotherapy-induced damage
TUMOR, NEUTROPENIA, BREAST CANCER, SECONDARY, ARREST
Data from this exploratory analysis provide further evidence of a trilaciclib-mediated antitumor immune response among patients with mTNBC [These findings support prior research indicating that, following transient G1 arrest, the proportion of immunosuppressive cells in the tumor microenvironment is decreased and effector T-cell function is enhanced [Data from diagnostic tumor samples collected at baseline showed that genes involved in immune cell activation were upregulated among trilaciclib responders, and there was a trend toward higher TIS scores. In general, although higher TIS scores are not associated with increased OS in breast cancer, they are associated with improved prognosis in those patients with the highest 10% of TIS scores [A trend for higher T-cell exhaustion at baseline may indicate that patients had a greater existing immune response and, consequently, higher existing T-cell infiltration into the tumor. Exhausted T-cell profiles in the tumor microenvironment [Additional analyses were conducted to compare results by PD-L1 status at baseline. Increased levels of peripheral memory CD8+ T cells and naïve CD8+ T cells were observed after two cycles in trilaciclib responders, regardless of PD-L1 status. However, greater peripheral immune responses and a trend toward an enriched TIS were identified in PD-L1-positive trilaciclib responders at baseline compared with non‑responders. These data support previous research showing that CDK4/6 inhibition promotes the formation of memory CD8+ T cells, which is proposed to occur via upregulation of MXD4 and resultant downregulation of Myc activity during T-cell activation [Limitations of this study include the small sample size, particularly in the responder subsets. Moreover, antitumor efficacy outcomes were not the primary study endpoints. The sample size was powered to show superiority among patients who received trilaciclib prior to GCb over those who received GCb alone for at least one primary endpoint (duration of severe neutropenia in cycle 1 or occurrence of severe neutropenia during the treatment period). As such, comparisons of secondary endpoints, including antitumor responses, should be considered exploratory and interpreted with caution. However, the findings of this hypothesis-generating analysis were consistent with, and supportive of, a previous exploratory analysis of the same study [Overall, these data contribute to a growing body of evidence that transient administration of trilaciclib prior to GCb may enhance antitumor efficacy by both protecting immune cells from chemotherapy-induced damage and modulating the composition and response of immune cell subsets. Data from ongoing clinical studies are critical to confirming the underlying immune mechanisms and to identifying biomarkers that will clearly distinguish between trilaciclib responders and non‑responders.