Monitoring changing patterns in HER2 addiction by liquid biopsy in advanced breast cancer patients.

Autor: Giordani E; Translational Oncology Research, IRCCS Regina Elena National Cancer Institute, Rome, Italy., Allegretti M; Translational Oncology Research, IRCCS Regina Elena National Cancer Institute, Rome, Italy., Sinibaldi A; Department of Basic and Applied Sciences for Engineering, SAPIENZA University of Rome, Rome, Italy., Michelotti F; Department of Basic and Applied Sciences for Engineering, SAPIENZA University of Rome, Rome, Italy., Ferretti G; Division of Medical Oncology 1, IRCCS Regina Elena National Cancer Institute, Rome, Italy., Ricciardi E; Translational Oncology Research, IRCCS Regina Elena National Cancer Institute, Rome, Italy., Ziccheddu G; Translational Oncology Research, IRCCS Regina Elena National Cancer Institute, Rome, Italy., Valenti F; Translational Oncology Research, IRCCS Regina Elena National Cancer Institute, Rome, Italy., Di Martino S; UOC Anatomy Pathology and Biobank, IRCCS Regina Elena National Cancer Institute, Istituti Fisioterapici Ospitalieri, Rome, Italy., Ercolani C; Pathology Unit, IRCCS Regina Elena National Cancer Institute, Rome, Italy., Giannarelli D; Facility of Epidemiology and Biostatistics, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy., Arpino G; Oncology Division, Department of Clinical Medicine and Surgery, University Federico II, Naples, Italy., Gori S; Medical Oncology, IRCCS-Sacro Cuore Don Calabria Hospital, Negrar di Valpolicella, Verona, Italy., Omarini C; Division of Medical Oncology, Department of Oncology and Hematology, University Hospital of Modena, Modena, Italy., Zambelli A; Oncology Unit, ASST Papa Giovanni XXIII, Bergamo, Italy., Bria E; Medical Oncology, Università Cattolica del Sacro Cuore, Rome, Italy.; Comprehensive Cancer Center, Fondazione Policlinico Universitario Agostino Gemelli, IRCCS, Rome, Italy., Paris I; Department of Woman and Child Health, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy., Buglioni S; Pathology Unit, IRCCS Regina Elena National Cancer Institute, Rome, Italy., Giacomini P; Precision Medicine Unit in Senology, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Largo Agostino Gemelli, 8, 00168, Roma, Italy. patrizio.giacomini@guest.policlinicogemelli.it., Fabi A; Precision Medicine Unit in Senology, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Largo Agostino Gemelli, 8, 00168, Roma, Italy.
Jazyk: angličtina
Zdroj: Journal of experimental & clinical cancer research : CR [J Exp Clin Cancer Res] 2024 Jun 29; Vol. 43 (1), pp. 182. Date of Electronic Publication: 2024 Jun 29.
DOI: 10.1186/s13046-024-03105-9
Abstrakt: Background: During targeted treatment, HER2-positive breast cancers invariably lose HER2 DNA amplification. In contrast, and interestingly, HER2 proteins may be either lost or gained. To longitudinally and systematically appreciate complex/discordant changes in HER2 DNA/protein stoichiometry, HER2 DNA copy numbers and soluble blood proteins (aHER2/sHER2) were tested in parallel, non-invasively (by liquid biopsy), and in two-dimensions, hence HER2-2D.
Methods: aHER2 and sHER2 were assessed by digital PCR and ELISA before and after standard-of-care treatment of advanced HER2-positive breast cancer patients (n=37) with the antibody-drug conjugate (ADC) Trastuzumab-emtansine (T-DM1).
Results: As expected, aHER2 was invariably suppressed by T-DM1, but this loss was surprisingly mirrored by sHER2 gain, sometimes of considerable entity, in most (30/37; 81%) patients. This unorthodox split in HER2 oncogenic dosage was supported by reciprocal aHER2/sHER2 kinetics in two representative cases, and an immunohistochemistry-high status despite copy-number-neutrality in 4/5 available post-T-DM1 tumor re-biopsies from sHER2-gain patients. Moreover, sHER2 was preferentially released by dying breast cancer cell lines treated in vitro by T-DM1. Finally, sHER2 gain was associated with a longer PFS than sHER2 loss (mean PFS 282 vs 133 days, 95% CI [210-354] vs [56-209], log-rank test p=0.047), particularly when cases (n=11) developing circulating HER2-bypass alterations during T-DM1 treatment were excluded (mean PFS 349 vs 139 days, 95% CI [255-444] vs [45-232], log-rank test p=0.009).
Conclusions: HER2 gain is adaptively selected in tumor tissues and recapitulated in blood by sHER2 gain. Possibly, an increased oncogenic dosage is beneficial to the tumor during anti-HER2 treatment with naked antibodies, but favorable to the host during treatment with a strongly cytotoxic ADC such as T-DM1. In the latter case, HER2-gain tumors may be kept transiently in check until alternative oncogenic drivers, revealed by liquid biopsy, bypass HER2. Whichever the interpretation, HER2-2D might help to tailor/prioritize anti-HER2 treatments, particularly ADCs active on aHER2-low/sHER2-low tumors.
Trial Registration: NCT05735392 retrospectively registered on January 31, 2023 https://www.
Clinicaltrials: gov/search?term=NCT05735392.
(© 2024. The Author(s).)
Databáze: MEDLINE
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