Determinants of response and molecular dynamics in HER2+ER+ breast cancers from the NA-PHER2 trial receiving HER2-targeted and endocrine therapies

Maurizio Callari, Matteo Dugo, Marco Barreca, Balázs Győrffy, Barbara Galbardi, Lucia Vigano, Alberta Locatelli, Chiara Dall’Ara, Marina Ferrarini, Giancarlo Bisagni, Marco Colleoni, Mauro Mansutti, Claudio Zamagni, Lucia Mastro, Stefania Zambelli, Antonio Frassoldati, Olivia Biasi, Lajos Pusztai, Pinuccia Valagussa, Giuseppe Viale, Luca Gianni () and Giampaolo Bianchini ()
Additional contact information
Maurizio Callari: Fondazione Michelangelo
Matteo Dugo: IRCCS San Raffaele Hospital
Marco Barreca: Fondazione Michelangelo
Balázs Győrffy: Semmelweis University
Barbara Galbardi: IRCCS San Raffaele Hospital
Lucia Vigano: IRCCS San Raffaele Hospital
Alberta Locatelli: IRCCS San Raffaele Hospital
Chiara Dall’Ara: IRCCS San Raffaele Hospital
Marina Ferrarini: IRCCS San Raffaele Hospital
Giancarlo Bisagni: AUSL – IRCCS
Marco Colleoni: IRCCS
Mauro Mansutti: Udine Academic Hospital
Claudio Zamagni: IRCCS Azienda Ospedaliero Universitaria
Lucia Mastro: Università di Genova
Stefania Zambelli: IRCCS San Raffaele Hospital
Antonio Frassoldati: Azienda Ospedaliera Universitaria S. Anna
Olivia Biasi: IRCCS
Lajos Pusztai: Yale School of Medicine
Pinuccia Valagussa: Fondazione Michelangelo
Giuseppe Viale: Fondazione Michelangelo
Luca Gianni: Fondazione Michelangelo
Giampaolo Bianchini: IRCCS San Raffaele Hospital

Nature Communications, 2025, vol. 16, issue 1, 1-15

Abstract: Abstract Improved outcomes in HER2+ female breast cancer have resulted from chemotherapy and anti-HER2 therapies. However, HER2+ER+ cancers exhibit lower response rates. The phase 2 NA-PHER2 trial (NCT02530424) investigated chemo-free preoperative HER2 blockade (trastuzumab + pertuzumab) and CDK4/6 inhibition (palbociclib) with or without endocrine therapy (fulvestrant) in HER2+ER+ breast cancer. Clinical endpoints (i.e. Ki67 dynamics and pathological complete response) were previously reported. Here we report on the biomarker analysis, secondary objective of the study. Through RNA sequencing and tumour infiltrating lymphocytes (TIL) assessment in serial biopsies, we identified biomarkers predictive of pCR or Day14 Ki67 response and unveiled treatment-induced molecular changes. High immune infiltration and low ER signalling correlated with pCR, while TP53 mutations associated with high Day14 Ki67. Stratification based on Ki67 at Day14 and at surgery defined three response groups (Ki67 HighHigh, LowHigh, LowLow), with divergent tumour and stroma expression dynamics. The HighHigh group showed dysfunctional immune infiltration and overexpression of therapeutic targets like PAK4 at baseline. The LowLow group exhibited a Luminal A phenotype by the end of treatment. This study expands our understanding of drivers and dynamics of HER2+ER+ tumour response, towards treatment tailoring.

Date: 2025
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DOI: 10.1038/s41467-025-57293-9

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