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However, ctDNA-RECIST (cRECIST) and ctDNA-guided End of Treatment (cEoT) are not applied routinely.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      To provide proof-of-concept for RECIST1.1\/cRECIST integration, HER2-positive metastatic breast cancer patients (\n                      <jats:italic>n<\/jats:italic>\n                      \u2009=\u200950) were enrolled in the multi-center prospective GIM21 study to receive Trastuzumab-emtansine (T-DM1). CT scans (113 tumor lesions) were longitudinally assessed for classical Objective Responses (ORs: progressive disease\/stable disease\/partial response\/complete response; PD\/SD\/PR\/CR) applying default RECIST 1.1 cut-offs (SD\/PD\u2009\u2265\u200920%; SD\/PR\u2009\u2264\u200930%). Likewise, bespoke NGS\/dPCR (78 genomic alterations; 466 time points) were converted into ctDNA-Objective Responses (cORs: cPD\/cSD\/cPR\/cCR) exploring wide cPD\/cSD\/cCR cut-off ranges, both default (RECIST 1.1-like) and alternative.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Whichever the cut-off, cORs were much deeper than ORs, leading to RECIST 1.1\/cRECIST divergence in 27 cPD-positive patients. Moreover, due to complex ctDNA trajectories (multiple successive ctDNA increases\/decreases, termed ctDNA waving), cPD (the earliest ctDNA increase) correlated with outcome in broad patient subsets but not individual patients. To deconvolute ctDNA waving, cPD was combined with three-point ctDNA\n                      <jats:italic>Tr<\/jats:italic>\n                      ends (\n                      <jats:italic>Tr<\/jats:italic>\n                      ), resulting in a personalized cEoT clinical algorithm that, once retrofitted to the 27 cPD-positive patient dataset, aligned with PFS much better than cPD (cEoT\/PFS vs cPD\/PFS linear regression: R\n                      <jats:sup>2<\/jats:sup>\n                      \u2009=\u20090.85 vs 0.35).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Even in difficult ctDNA scenarios, the cEoT algorithm may help to: (a) predict treatment efficacy during drug development, (b) adaptively randomize for patient-specific, timely treatment switch in clinical trials, and (c) prevent premature treatment withdrawal in long-responders. Future randomized studies are warranted for cRECIST\/RECIST 1.1 integration\/personalization in different tumors\/settings.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Trial registration<\/jats:title>\n                    <jats:p>NCT05735392.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/s13046-025-03605-2","type":"journal-article","created":{"date-parts":[[2026,1,20]],"date-time":"2026-01-20T14:04:34Z","timestamp":1768917874000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Circulating tumor DNA and Response Evaluation Criteria In Solid Tumors: ctDNA-RECIST proof-of-concept in HER2-positive metastatic breast cancer"],"prefix":"10.1186","volume":"45","author":[{"given":"Alessandra","family":"Fabi","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elena","family":"Giordani","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elena","family":"Ricciardi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Grazia","family":"Arpino","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matteo","family":"Allegretti","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gianluigi","family":"Ferretti","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claudia","family":"Omarini","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alberto","family":"Zambelli","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chiara","family":"Mandoj","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrea","family":"Botticelli","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emilio","family":"Bria","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefania","family":"Gori","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luisa","family":"Carbognin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ida","family":"Paris","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giovanni","family":"Scambia","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesco","family":"Cognetti","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Diana","family":"Giannarelli","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patrizio","family":"Giacomini","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,1,20]]},"reference":[{"key":"3605_CR1","doi-asserted-by":"publisher","first-page":"228","DOI":"10.1016\/j.ejca.2008.10.026","volume":"45","author":"EA Eisenhauer","year":"2009","unstructured":"Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, et al. 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Written informed consent was obtained from all patients before study entry.Not applicable.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"A.F.: consultant or advisor for Roche, Lilly, Novartis, AstraZeneca, Pfizer, Seagen, Gilead, MSD, Menarini Stemline, Domp\u00e8 Biotech; speaker honoraria from Astra Zeneca, Roche, Lilly, Novartis, Gilead, Pfizer, Daiichi Sankyo Exact Sciences; grant support (to the Institution) by Astra Zeneca, Roche. GA: personal fees from Novartis, Lilly; grants and personal fees from Roche; grants, personal fees, and nonfinancial support from Pfizer; grants, personal fees, and nonfinancial support from AstraZeneca; and personal fees from Daichi. E.B.: grants or contracts from Astra-Zeneca, Roche; honoraria for lectures from Merck-Sharp & Dome, Astra-Zeneca, Pfizer, Eli-Lilly, Bristol-Myers Squibb, Novartis, Takeda and Roche; member of Data Safety Monitoring Board or Advisory Board of Merck-Sharp & Dome, Pfizer, Novartis, Bristol-Myers Squibb, Astra-Zeneca, Roche, Amgen and Celltrion. F.C.: consultant for Exact Science and AstraZeneca.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"67"}}