5-year outcomes of chemotherapy de-escalation in HER2-positive early breast cancer and exploratory circulating tumor DNA analyses from the randomized phase 2 PHERGain trial

PHERGain was a randomized, non-comparative phase 2 trial evaluating a positron 18F-fluorodeoxyglucose-positron emission tomography (18F-FDG-PET)-guided, pathological complete response (pCR)-adapted strategy to omit chemotherapy in HER2-positive early breast cancer. Female patients with HER2-positive stages I–IIIA operable breast cancer (tumor size ≥ 1.5 cm) were randomized to receive chemotherapy plus trastuzumab and pertuzumab (HP; group A) or HP ± endocrine therapy (group B). In group B, treatment was adapted according to 18F-FDG-PET response after two cycles and pCR, with chemotherapy administered to nonresponders or patients without pCR. We previously reported that this de-escalation approach revealed a 3-year invasive disease-free survival (iDFS) of 94.3% (95% confidence interval (CI): 90.9 to 96.8) in group B. Here we report the prespecified secondary endpoint, 5-year iDFS and exploratory circulating tumor DNA (ctDNA) findings. After a median follow-up of 5.6 years, the 5-year iDFS was 89.5% (95% CI: 85.7 to 93.4) in group B (n = 267) and 92.4% (95% CI: 86.7 to 98.5) among 18F-FDG-PET responders achieving pCR without chemotherapy (n = 86), with one distant recurrence. The latter estimate describes a long-term outcome in a post-randomization subgroup defined by 18F-FDG-PET response and pCR and should be interpreted as descriptive rather than as causal effects of omitting chemotherapy. Detectable ctDNA at baseline or during treatment was associated with inferior iDFS, whereas ctDNA clearance correlated with higher pCR rates and improved long-term outcomes. These findings continue to support the clinical validity of an 18F-FDG-PET-guided, pCR-adapted approach and suggest a potential role for ctDNA in refining treatment individualization. ClinicalTrials.gov identifier: NCT03161353 . A 5-year secondary analysis of the phase 2 PHERGain trial supports the clinical utility of a PET-guided adaptive strategy for treatment de-escalation in HER2-positive early breast cancer and provides circulating tumor DNA insights that could inform further treatment approaches.

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Journal
Nature Medicine
Published
2026-10-29
DOI
https://doi.org/10.1038/s41591-026-04723-w
Primary Topic
Breast Cancer Treatment Studies
Type
article
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article

5-year outcomes of chemotherapy de-escalation in HER2-positive early breast cancer and exploratory circulating tumor DNA analyses from the randomized phase 2 PHERGain trial

Serena Di Cosimo, Daniel Alcalá-López, Frederik Marmé, Begoña Bermejo et al.
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Nature Medicine
Breast Cancer Treatment Studies
article

5-year outcomes of chemotherapy de-escalation in HER2-positive early breast cancer and exploratory circulating tumor DNA analyses from the randomized phase 2 PHERGain trial

Serena Di Cosimo, Daniel Alcalá-López, Frederik Marmé, Begoña Bermejo, Géraldine Gebhart, Sofia Azambuja Braga, Cristina Reboredo, Lucia Sanz, Giulia Notini, Antonio Llombart‐Cussac, María Gión, Mario Mancino, Cinta Rosa Albacar, Manuel Ruíz‐Borrego, Jose Antonio Guerrero-Martinez, Javier Cortés, Marco Angelo Colleoni, José Rodríguez-Morató, Florence Dalenc, Agostina Stradella, Ana Amaya-Garrido, Vega Iranzo, Santiago Escrivá-de-Romaní, Noelia Martínez-Jáñez, Elena Martínez-García, Nuria Ribelles, Leonardo Bruno Mina, Gabriele Antonarelli, Aleix Prat, José Manuel Pérez-García, Juan Jose Garcia, Alba Meya, Peter Schmid, Derek Dustin
article en

Abstract

PHERGain was a randomized, non-comparative phase 2 trial evaluating a positron 18F-fluorodeoxyglucose-positron emission tomography (18F-FDG-PET)-guided, pathological complete response (pCR)-adapted strategy to omit chemotherapy in HER2-positive early breast cancer. Female patients with HER2-positive stages I–IIIA operable breast cancer (tumor size ≥ 1.5 cm) were randomized to receive chemotherapy plus trastuzumab and pertuzumab (HP; group A) or HP ± endocrine therapy (group B). In group B, treatment was adapted according to 18F-FDG-PET response after two cycles and pCR, with chemotherapy administered to nonresponders or patients without pCR. We previously reported that this de-escalation approach revealed a 3-year invasive disease-free survival (iDFS) of 94.3% (95% confidence interval (CI): 90.9 to 96.8) in group B. Here we report the prespecified secondary endpoint, 5-year iDFS and exploratory circulating tumor DNA (ctDNA) findings. After a median follow-up of 5.6 years, the 5-year iDFS was 89.5% (95% CI: 85.7 to 93.4) in group B (n = 267) and 92.4% (95% CI: 86.7 to 98.5) among 18F-FDG-PET responders achieving pCR without chemotherapy (n = 86), with one distant recurrence. The latter estimate describes a long-term outcome in a post-randomization subgroup defined by 18F-FDG-PET response and pCR and should be interpreted as descriptive rather than as causal effects of omitting chemotherapy. Detectable ctDNA at baseline or during treatment was associated with inferior iDFS, whereas ctDNA clearance correlated with higher pCR rates and improved long-term outcomes. These findings continue to support the clinical validity of an 18F-FDG-PET-guided, pCR-adapted approach and suggest a potential role for ctDNA in refining treatment individualization. ClinicalTrials.gov identifier: NCT03161353 . A 5-year secondary analysis of the phase 2 PHERGain trial supports the clinical utility of a PET-guided adaptive strategy for treatment de-escalation in HER2-positive early breast cancer and provides circulating tumor DNA insights that could inform further treatment approaches.

Nature Medicine
Université Libre de Bruxelles (BE), Vita-Salute San Raffaele University (IT), Universitat de València (ES), Queen Mary University of London (GB), University of Milan (IT), Heidelberg University (DE), Barts Health NHS Trust (GB), Universidad Cardenal Herrera CEU (ES), Instituto de Salud Carlos III (ES), Institut Jules Bordet (BE), Institut d'Investigació Biomédica de Bellvitge (ES), Hospital Clínico Universitario de Valencia (ES), Instituto Oncológico Dr. Rosell (ES), Fundación para el Fomento de la Investigación Sanitaria y Biomédica de la Comunitat Valenciana (ES), Institut universitaire du cancer de Toulouse Oncopole (FR), Guardant (United States) (US), Institut de Recerca Biomèdica Catalunya Sud (ES), MedSIR (Spain) (ES), Institut Català d'Oncologia (ES), Hospital Clínic de Barcelona (ES), Hospital Arnau de Vilanova (ES), Instituto Ramón y Cajal de Investigación Sanitaria (ES), Vall d'Hebron Hospital Universitari (ES), Hospital General Universitario De Valencia (ES), IRCCS Ospedale San Raffaele (IT), Complexo Hospitalario Universitario A Coruña (ES), Hospital Universitari Sant Joan de Reus (ES), Hospital Universitario Virgen del Rocío (ES), Fondazione IRCCS Istituto Nazionale dei Tumori (IT), Hospital Clínico Universitario Virgen de la Victoria (ES), INCLIVA Health Research Institute (ES), Centro de Investigación Biomédica en Red de Cáncer (ES), Consorci Institut D'Investigacions Biomediques August Pi I Sunyer (ES), Hospital Universitario Ramón y Cajal (ES), Instituto de Investigación Biomédica de Málaga (ES), Medizinische Fakultät Mannheim (DE), Vall d'Hebron Institute of Oncology (ES), Barts Cancer Institute (GB), IDCQ Hospitales y Sanidad, S.L.U. (ES), European Institute of Oncology (IT), Universitat de Barcelona (ES), Universidad Europea de Madrid (ES)
F. Hoffmann-La Roche
Good health and well-being
Openalex Percentile: Top 16%
Breast Cancer Treatment Studies
DOIOpen Access PDFOpenAlex
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