Discussion
toxicity, TNBC, tumors
TUMORS, METASTATIC BREAST CANCER, TUMOR ANGIOGENESIS
In this prospective umbrella trial, we evaluated the feasibility and clinical utility of the subtyping-based precision strategy in heavily pretreated metastatic TNBC patients. Our work established a subtyping platform to navigate the precision treatment of TNBC based on the recognition of molecular characteristics instead of genomic alterations. The main purpose of this work was to highlight the superiority of the platform, not the superiority of a specific drug or regimen, as future advances in drug development could supplant the leading drugs. Notable accomplishments in this study include the following: (1) we demonstrated that TNBC subtyping combined with NGS was clinically feasible for matching and enrolling patients, with new biomarker-driven treatment arms being introduced and conducted simultaneously after previous arms reached a futility or efficacy boundary; (2) promising outcomes were confirmed in a subtype and genomic characteristics dual-directed therapeutic strategy, and these outcomes can be translated into long-term survival benefit; (3) integrated genomic and clinicopathological profiling illustrated associations of clinical and genomic parameters with treatment efficacy, and for arms with unsatisfactory response, novel ADCs were tested, providing clues for further exploration.The FUTURE study recruited 141 TNBC patients. Unlike most umbrella trials focusing on specific therapies,In addition, patients enrolled in this study were heavily pretreated and chemotherapy resistant with a short disease-free interval and duration of first-line therapy. In this study, the ORR reached nearly 30%, the median PFS reached 3.4 months, and the median OS reached 10.7 months, all of which were more favorable than the outcomes of traditional chemotherapy in the heavily pretreated patients of the TNBC population (ORR of 5%, median PFS of 1.7 months, and median OS of 6.7 months).Arms A, C, E, and G demonstrated promising outcomes. For arm C, the results for PD-1 blockade plus chemotherapy in the IM subtype showed the highest ORR reported in a prospective trial conducted with heavily pretreated metastatic TNBC patients. A highlight of arm C was the usage of CD8 to define the IM subtype and match “immune-hot” tumors, validating the initial hypothesis that we proposed.BLIS is characterized by high expression of the VEGF signature, which is associated with tumor angiogenesis and poor prognosis.Interestingly, arms A and G showed promising outcomes in a small sample size. In rare instances (2%–4%), patients with metastatic breast cancer have By comparison, treatment efficacy was unsatisfactory in arms B, D, and F. For BLIS with FUTURE is a pilot study designed to generate clues for clinical practice. Owing to the design of this umbrella trial, the number of patients is relatively small in some arms and unbalanced between arms, which has been discussed above. Notwithstanding the relatively limited sample size, this study offers valuable insights into tailoring and bolstering precision therapy through prospective molecular subtyping selection. Next, direct comparison with other chemotherapy approaches was not available in this trial because of its noncomparative design and the lack of accessible treatment options for the heavily pretreated patients of this population. Our randomized controlled umbrella FUTURE-SUPER trial (NCT04395989) is currently in progress. Finally, although PFS was not as satisfactory as sacituzumab govitecan, the primary endpoints ORR and OS were both comparable.Collectively, the subtyping-based and genomic sequencing-guided strategy promotes promising efficacy with manageable toxicity in patients with heavily pretreated metastatic TNBC. As a dynamic and ongoing platform for novel targeted regimens, FUTURE can enable efficient testing of potential new drug–biomarker combinations in the context of subtyping, generating clues for further validation in expansion trials.