Discussion
headaches, fatigue, breast cancer, toxicity, toxicities, telangiectasias, later-onset, skin rash, nasal congestion, HHT, later-onset anemia, epistaxis
BREAST CANCER, ADVERSE EVENTS, SECONDARY, PROLIFERATIVE, GINGIVAL HEMORRHAGE, EPISTAXIS, HHT
This study met its primary endpoint of determining the MTD, RP2D, and rates of adverse events associated with the combination of letrozole with everolimus and carotuximab ± goserelin. All agents were tolerated at their single-agent doses. The toxicity profile was dominated by carotuximab and phenocopied HHT. Despite the paucity of adverse events greater than grade 2, all patients experienced adverse events that accumulated over time leading to frequent dose reductions. One should acknowledge the excellent performance status of patients with newly diagnosed breast cancer as well as the fact that endocrine combinations with novel oral agents, particularly inhibitors of the cyclin dependent kinase 4 and 6 (CDK4/6), can yield similarly high rates of molecular downstaging with fewer toxicities [Pharmacokinetic analyses, which constituted a secondary objective of the study, show that, despite the targeted nature of carotuximab and everolimus, interactions did arise. The accumulation of carotuximab in the extravascular space with successive administrations may explain the later-onset anemia (typically seen after cycle 3) and the rising frequency and severity of adverse events associated with carotuximab (headaches, fatigue, epistaxis, gingival hemorrhage, nasal congestion, and telangiectasias). Carotuximab also accelerated the biodistribution of everolimus which probably underpins a pharmacodynamic interaction, in terms of significant downregulation of a proliferative gene expression signature as well as causation of synergistic adverse events (fatigue, skin rash, gingival hemorrhage). The long interval required for letrozole to reach steady state and the accumulation with repeated dosing may explain the later-onset of adverse events typically associated with this agent.In terms of assessing the antitumor activity of preoperative endocrine therapy and especially combinatorial regimens, uniform criteria for optimal patient selection, endpoints to capture the activity of preoperative endocrine therapy, and biomarkers to escalate or de-escalate therapy have not been adopted.Our results and other trials [Recognizing that the achievement of pCR is an endpoint that does not align with the nature of luminal breast cancer and conventional pathologic criteria do not capture the gene expression changes induced by preoperative endocrine therapy, other, mostly proliferation-based biomarkers have been used [In conclusion, letrozole, everolimus, and carotuximab ± goserelin were tolerated in combination at their single-agent doses. Escalating the number of targeted agents in combinatorial preoperative regimens, may enhance the toxicities due to unaccounted interactions while the respective increments in antitumor activity may remain elusive.