Unraveling the clinicopathological and molecular changes induced by neoadjuvant chemotherapy and endocrine therapy in hormone receptor-positive/HER2-low and HER2-0 breast cancer.

HER2 dynamics HER2-low hormone receptor-positive neoadjuvant chemotherapy neoadjuvant endocrine therapy

Journal

ESMO open
ISSN: 2059-7029
Titre abrégé: ESMO Open
Pays: England
ID NLM: 101690685

Informations de publication

Date de publication:
28 Jun 2024
Historique:
received: 28 12 2023
revised: 16 04 2024
accepted: 28 05 2024
medline: 30 6 2024
pubmed: 30 6 2024
entrez: 29 6 2024
Statut: aheadofprint

Résumé

The characterization and comparison of gene expression and intrinsic subtype (IS) changes induced by neoadjuvant chemotherapy (NACT) and endocrine therapy in hormone receptor-positive (HR+)/human epidermal growth factor receptor 2 (HER2)-low versus HR+/HER2-0 breast cancer (BC) has not been conducted so far. Most evidence on the association of HER2 status with pathologic responses and prognosis in HR+/HER2-negative BC is controversial and restricted to NACT-treated disease. Similarly, a temporal heterogeneity in HER2 status has been described only with NACT. We retrospectively recruited a consecutive cohort of 186 patients with stage I-IIIB HR+/HER2-negative BC treated with neoadjuvant therapy (NAT). Available diagnostic biopsies and surgical samples were characterized for main pathological features, PAM50 IS and ROR-P score, and gene expression. Associations with pathologic complete response, residual cancer burden-0/I, event-free survival (EFS) and overall survival (OS) based on HER2 status were assessed. Pre/post pathologic/molecular changes were analyzed in matched samples. The HER2-low (62.9%) and HER2-0 (37.1%) cohorts did not differ significantly in main baseline features, treatments administered, breast-conserving surgery, pathologic complete response and residual cancer burden-0/I rates, EFS, and OS. NAT induced, regardless of HER2 status, a significant reduction of estrogen receptor/progesterone receptor and Ki67 levels, a down-regulation of PAM50 proliferation- and luminal-related genes/signatures, an up-regulation of selected immune genes, and a shift towards less aggressive IS and lower ROR-P. Moreover, 25% of HER2-0 changed to HER2-low and 34% HER2-low became HER2-0. HER2 shifts were significant after NACT (P < 0.001), not neoadjuvant endocrine therapy (P = 0.063), with consistent ERBB2 mRNA level dynamics. HER2 changes were not associated with EFS/OS. HER2-low and HER2-0 status change after NAT in ∼30% of cases, mostly after NACT. Targeted adjuvant strategies should be investigated accordingly. Molecular downstaging with current chemo/endocrine agents and immunotherapy should not rely on HER2 immunohistochemical levels in HR+/HER2-negative BC. Instead, HER2-low-targeted approaches should be explored to pursue more effective and/or less toxic dimensional downstaging.

Sections du résumé

BACKGROUND BACKGROUND
The characterization and comparison of gene expression and intrinsic subtype (IS) changes induced by neoadjuvant chemotherapy (NACT) and endocrine therapy in hormone receptor-positive (HR+)/human epidermal growth factor receptor 2 (HER2)-low versus HR+/HER2-0 breast cancer (BC) has not been conducted so far. Most evidence on the association of HER2 status with pathologic responses and prognosis in HR+/HER2-negative BC is controversial and restricted to NACT-treated disease. Similarly, a temporal heterogeneity in HER2 status has been described only with NACT.
METHODS METHODS
We retrospectively recruited a consecutive cohort of 186 patients with stage I-IIIB HR+/HER2-negative BC treated with neoadjuvant therapy (NAT). Available diagnostic biopsies and surgical samples were characterized for main pathological features, PAM50 IS and ROR-P score, and gene expression. Associations with pathologic complete response, residual cancer burden-0/I, event-free survival (EFS) and overall survival (OS) based on HER2 status were assessed. Pre/post pathologic/molecular changes were analyzed in matched samples.
RESULTS RESULTS
The HER2-low (62.9%) and HER2-0 (37.1%) cohorts did not differ significantly in main baseline features, treatments administered, breast-conserving surgery, pathologic complete response and residual cancer burden-0/I rates, EFS, and OS. NAT induced, regardless of HER2 status, a significant reduction of estrogen receptor/progesterone receptor and Ki67 levels, a down-regulation of PAM50 proliferation- and luminal-related genes/signatures, an up-regulation of selected immune genes, and a shift towards less aggressive IS and lower ROR-P. Moreover, 25% of HER2-0 changed to HER2-low and 34% HER2-low became HER2-0. HER2 shifts were significant after NACT (P < 0.001), not neoadjuvant endocrine therapy (P = 0.063), with consistent ERBB2 mRNA level dynamics. HER2 changes were not associated with EFS/OS.
CONCLUSIONS CONCLUSIONS
HER2-low and HER2-0 status change after NAT in ∼30% of cases, mostly after NACT. Targeted adjuvant strategies should be investigated accordingly. Molecular downstaging with current chemo/endocrine agents and immunotherapy should not rely on HER2 immunohistochemical levels in HR+/HER2-negative BC. Instead, HER2-low-targeted approaches should be explored to pursue more effective and/or less toxic dimensional downstaging.

Identifiants

DOI: 10.1016/j.esmoop.2024.103619 PMID: 38943737
pubmed: 38943737
pii: S2059-7029(24)01388-7
doi: 10.1016/j.esmoop.2024.103619
pii:
doi:

Types de publication

Journal Article

Langues

eng

Sous-ensembles de citation

IM

Pagination

103619

Informations de copyright

Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.

Auteurs

F Schettini (F)

Translational Genomics and Targeted Therapies in Solid Tumors, August Pi I Sunyer Biomedical Research Institute (IDIBAPS), Barcelona; Medical Oncology Department, Hospital Clinic of Barcelona, Barcelona, Spain. Electronic address: schettini@recerca.clinic.cat.

S Nucera (S)

Translational Genomics and Targeted Therapies in Solid Tumors, August Pi I Sunyer Biomedical Research Institute (IDIBAPS), Barcelona; Department of Human Pathology "G. Barresi", University of Messina, Messina.

F Brasó-Maristany (F)

Translational Genomics and Targeted Therapies in Solid Tumors, August Pi I Sunyer Biomedical Research Institute (IDIBAPS), Barcelona. Electronic address: https://twitter.com/fara_bm.

I De Santo (I)

Medical Oncology Unit, Ave Gratia Plena Hospital, San Felice a Cancello (CE), Italy.

T Pascual (T)

Translational Genomics and Targeted Therapies in Solid Tumors, August Pi I Sunyer Biomedical Research Institute (IDIBAPS), Barcelona; Medical Oncology Department, Hospital Clinic of Barcelona, Barcelona, Spain; SOLTI Cooperative Research Group, Barcelona. Electronic address: https://twitter.com/TomasPascualMD.

M Bergamino (M)

Medical Oncology Department, Catalan Institute of Oncology, Badalona. Electronic address: https://twitter.com/MilanaBeSirven.

P Galván (P)

Translational Genomics and Targeted Therapies in Solid Tumors, August Pi I Sunyer Biomedical Research Institute (IDIBAPS), Barcelona.

B Conte (B)

Translational Genomics and Targeted Therapies in Solid Tumors, August Pi I Sunyer Biomedical Research Institute (IDIBAPS), Barcelona; Medical Oncology Department, Hospital Clinic of Barcelona, Barcelona, Spain.

E Seguí (E)

Translational Genomics and Targeted Therapies in Solid Tumors, August Pi I Sunyer Biomedical Research Institute (IDIBAPS), Barcelona; Medical Oncology Department, Hospital Clinic of Barcelona, Barcelona, Spain.

I García Fructuoso (I)

Translational Genomics and Targeted Therapies in Solid Tumors, August Pi I Sunyer Biomedical Research Institute (IDIBAPS), Barcelona; Medical Oncology Department, Hospital Clinic of Barcelona, Barcelona, Spain.

R Gómez Bravo (R)

Translational Genomics and Targeted Therapies in Solid Tumors, August Pi I Sunyer Biomedical Research Institute (IDIBAPS), Barcelona; Medical Oncology Department, Hospital Clinic of Barcelona, Barcelona, Spain.

P Rivera (P)

Translational Genomics and Targeted Therapies in Solid Tumors, August Pi I Sunyer Biomedical Research Institute (IDIBAPS), Barcelona; Medical Oncology Department, Hospital Clinic of Barcelona, Barcelona, Spain.

A B Rodríguez (AB)

Translational Genomics and Targeted Therapies in Solid Tumors, August Pi I Sunyer Biomedical Research Institute (IDIBAPS), Barcelona; Medical Oncology Department, Hospital Clinic of Barcelona, Barcelona, Spain.

O Martínez-Sáez (O)

Translational Genomics and Targeted Therapies in Solid Tumors, August Pi I Sunyer Biomedical Research Institute (IDIBAPS), Barcelona; Medical Oncology Department, Hospital Clinic of Barcelona, Barcelona, Spain; Faculty of Medicine and Health Sciences, University of Barcelona, Barcelona. Electronic address: https://twitter.com/OlgaMartnezSez1.

S Ganau (S)

Department of Radiology, Diagnosis Imaging Center, Hospital Clinic of Barcelona, Barcelona.

E Sanfeliu (E)

Translational Genomics and Targeted Therapies in Solid Tumors, August Pi I Sunyer Biomedical Research Institute (IDIBAPS), Barcelona; Faculty of Medicine and Health Sciences, University of Barcelona, Barcelona; Department of Pathology, Biomedical Diagnostic Center, Hospital Clinic of Barcelona, Barcelon.

B González-Farre (B)

Department of Pathology, Biomedical Diagnostic Center, Hospital Clinic of Barcelona, Barcelon.

M J Vidal Losada (MJ)

Translational Genomics and Targeted Therapies in Solid Tumors, August Pi I Sunyer Biomedical Research Institute (IDIBAPS), Barcelona; Medical Oncology Department, Hospital Clinic of Barcelona, Barcelona, Spain; SOLTI Cooperative Research Group, Barcelona; Faculty of Medicine and Health Sciences, University of Barcelona, Barcelona. Electronic address: https://twitter.com/MVidalMD.

B Adamo (B)

Translational Genomics and Targeted Therapies in Solid Tumors, August Pi I Sunyer Biomedical Research Institute (IDIBAPS), Barcelona; Medical Oncology Department, Hospital Clinic of Barcelona, Barcelona, Spain.

I Cebrecos (I)

Faculty of Medicine and Health Sciences, University of Barcelona, Barcelona; Department of Obstetrics and Gynecology, Hospital Clinic of Barcelona, Barcelona.

E Mension (E)

Department of Obstetrics and Gynecology, Hospital Clinic of Barcelona, Barcelona.

G Oses (G)

Radiation Oncology Department, Hospital Clínic de Barcelona, Barcelona.

P Jares (P)

Translational Genomics and Targeted Therapies in Solid Tumors, August Pi I Sunyer Biomedical Research Institute (IDIBAPS), Barcelona; Faculty of Medicine and Health Sciences, University of Barcelona, Barcelona; Department of Pathology, Biomedical Diagnostic Center, Hospital Clinic of Barcelona, Barcelon.

S Vidal-Sicart (S)

Department of Nuclear Medicine, Diagnosis Imaging Center, Hospital Clinic of Barcelona, Barcelona.

M Mollà (M)

Translational Genomics and Targeted Therapies in Solid Tumors, August Pi I Sunyer Biomedical Research Institute (IDIBAPS), Barcelona; Radiation Oncology Department, Hospital Clínic de Barcelona, Barcelona.

M Muñoz (M)

Translational Genomics and Targeted Therapies in Solid Tumors, August Pi I Sunyer Biomedical Research Institute (IDIBAPS), Barcelona; Medical Oncology Department, Hospital Clinic of Barcelona, Barcelona, Spain; SOLTI Cooperative Research Group, Barcelona; Faculty of Medicine and Health Sciences, University of Barcelona, Barcelona. Electronic address: https://twitter.com/MuozMateu.

A Prat (A)

Translational Genomics and Targeted Therapies in Solid Tumors, August Pi I Sunyer Biomedical Research Institute (IDIBAPS), Barcelona; Faculty of Medicine and Health Sciences, University of Barcelona, Barcelona; Institute of Cancer and Blood Diseases, Hospital Clinic of Barcelona, Barcelona; Breast Cancer Unit, Institute of Oncology Barcelona (IOB) - Quirónsalud, Barcelona; Reveal Genomic, Barcelona, Spain. Electronic address: alprat@clinic.cat.

Classifications MeSH