Circulating tumor DNA and Response Evaluation Criteria In Solid Tumors: ctDNA-RECIST proof-of-concept in HER2-positive metastatic breast cancer

Background: Response Evaluation Criteria In Solid Tumors (RECIST 1.1) and circulating tumor DNA (ctDNA) recapitulate and anticipate response to treatment, respectively. However, no ctDNA-RECIST (cRECIST) guidelines have been formally implemented in clinical practice so far. Methods: For first proof-of-principle, HER2-positive metastatic breast cancer patients (n=50) were enrolled in the multi-center prospective GIM21 study to receive Trastuzumab-emtansine (T-DM1), and were monitored for Objective Responses, e.g. ORs (progressive disease, stable disease, partial response, complete response; PD/SD/PR/CR) vs ctDNA-ORs (cORs: cPD/cSD/cPR/cCR). Standard OR cut-offs (SD/PD≥20% and SD/PR≤30%) were applied to cORs by default, or tentatively relaxed. Results: Whichever the cut-off, bespoke NGS/dPCR (78 ctDNAs; 466 measurements) and CT scans (113 tumor lesions) revealed much deeper cORs than ORs, leading to RECIST 1.1/cRECIST divergence in 27 cPD-positive patients. Yet, OR/cOR integration remained feasible at default/common cut-offs, as shown by correlation between fast cPD and poor OR/PFS. Although a satisfactory coarse patient classifier, cPD was unfortunately confounded by patient-specific, post-cPD ctDNA increases/decreases (ctDNA waving). Then, to personalize outcome prediction, two-point cRECIST comparisons (response vs baseline/nadir) were replaced by a novel non-cRECIST variable measuring three-point Tr ends ( Tr ). Remarkably, the duration of the first post-cPD Tr drop correlated with the timing of PD in 15/15 evaluable patients (R ² =0.76). Conclusions: Combined, cRECIST (cPD) and Tr may help to: (a) predict treatment efficacy during early drug development, (b) randomize for timely treatment switch in clinical trials, and (c) prevent premature treatment withdrawal in long-responders undergoing ctDNA waving. Future prospective studies are warranted for cRECIST/RECIST 1.1 integration/personalization in different tumors/settings. Trial registration: NCT05735392.