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HER2-enriched subtype and novel molecular subgroups drive aromatase inhibitor resistance and an increased risk of relapse in early ER+/HER2+ breast cancer

HER2-enriched subtype and novel molecular subgroups drive aromatase inhibitor resistance and an increased risk of relapse in early ER+/HER2+ breast cancer
HER2-enriched subtype and novel molecular subgroups drive aromatase inhibitor resistance and an increased risk of relapse in early ER+/HER2+ breast cancer

Background: oestrogen receptor positive/ human epidermal growth factor receptor positive (ER+/HER2+) breast cancers (BCs) are less responsive to endocrine therapy than ER+/HER2- tumours. Mechanisms underpinning the differential behaviour of ER+HER2+ tumours are poorly characterised. Our aim was to identify biomarkers of response to 2 weeks’ presurgical AI treatment in ER+/HER2+ BCs. 

Methods: all available ER+/HER2+ BC baseline tumours (n=342) in the POETIC trial were gene expression profiled using BC360™ (NanoString) covering intrinsic subtypes and 46 key biological signatures. Early response to AI was assessed by changes in Ki67 expression and residual Ki67 at 2 weeks (Ki67 2wk). Time-To-Recurrence (TTR) was estimated using Kaplan-Meier methods and Cox models adjusted for standard clinicopathological variables. New molecular subgroups (MS) were identified using consensus clustering. Findings: HER2-enriched (HER2-E) subtype BCs (44.7% of the total) showed poorer Ki67 response and higher Ki67 2wk (p<0.0001) than non-HER2-E BCs. High expression of ERBB2 expression, homologous recombination deficiency (HRD) and TP53 mutational score were associated with poor response and immune-related signatures with High Ki67 2wk. Five new MS that were associated with differential response to AI were identified. HER2-E had significantly poorer TTR compared to Luminal BCs (HR 2.55, 95% CI 1.14–5.69; p=0.0222). The new MS were independent predictors of TTR, adding significant value beyond intrinsic subtypes. 

Interpretation: our results show HER2-E as a standardised biomarker associated with poor response to AI and worse outcome in ER+/HER2+. HRD, TP53 mutational score and immune-tumour tolerance are predictive biomarkers for poor response to AI. Lastly, novel MS identify additional non-HER2-E tumours not responding to AI with an increased risk of relapse. 

Funding: Cancer Research UK (CRUK/07/015).

Aromatase Inhibitors, Biomarkers, Tumor/metabolism, Breast Neoplasms/drug therapy, Clinical Trials as Topic, Female, Humans, Ki-67 Antigen/genetics, Neoplasm Recurrence, Local/genetics, Receptor, ErbB-2/genetics, Receptors, Estrogen/genetics, Receptors, Progesterone/metabolism
2352-3964
Bergamino, Milana A.
49b76d4b-d6d5-40aa-9e3e-cfb56f558054
López-Knowles, Elena
ef44240d-77e2-4779-9053-3ffaf3055378
Morani, Gabriele
889f02a5-3ff2-4bbc-b86b-3e60fb052e96
Tovey, Holly
2568e1cc-a42c-44e7-8647-3e50f3a58a46
Kilburn, Lucy
df00b0c7-a52d-4241-97af-2ee1c20c08a5
Schuster, Eugene F
64a16431-a0c8-46f0-add8-97406cc7419b
Alataki, Anastasia
721015a0-9487-4fbd-be17-c1b2e03e1497
Hills, Margaret
a1994a99-e82e-44db-b3c4-b0ffa78a431b
Xiao, Hui
c70e695a-d56c-418b-a744-b1a0a594b41d
Holcombe, Chris
f9196a8b-3f04-49cf-aa7b-e0a3e02caa57
Skene, Anthony
65bb0e2f-77a8-4b01-bc42-ce714dc24b94
Robertson, John F
21acd356-2818-4824-b7c7-f5ba62439d15
Smith, Ian E
f2717374-4fc3-4dce-83b3-8f6128ae82cf
Bliss, Judith M
32216b02-f161-4aa5-8a6c-7777c440a458
Dowsett, Mitch
39a1ba62-b1de-478b-bcc6-0a169c415e8e
Cheang, Maggie C U
6074a68e-f537-42c2-aa30-d9d6d1012969
Cutress, Ramsey
68ae4f86-e8cf-411f-a335-cdba51797406
POETIC investigators
Bergamino, Milana A.
49b76d4b-d6d5-40aa-9e3e-cfb56f558054
López-Knowles, Elena
ef44240d-77e2-4779-9053-3ffaf3055378
Morani, Gabriele
889f02a5-3ff2-4bbc-b86b-3e60fb052e96
Tovey, Holly
2568e1cc-a42c-44e7-8647-3e50f3a58a46
Kilburn, Lucy
df00b0c7-a52d-4241-97af-2ee1c20c08a5
Schuster, Eugene F
64a16431-a0c8-46f0-add8-97406cc7419b
Alataki, Anastasia
721015a0-9487-4fbd-be17-c1b2e03e1497
Hills, Margaret
a1994a99-e82e-44db-b3c4-b0ffa78a431b
Xiao, Hui
c70e695a-d56c-418b-a744-b1a0a594b41d
Holcombe, Chris
f9196a8b-3f04-49cf-aa7b-e0a3e02caa57
Skene, Anthony
65bb0e2f-77a8-4b01-bc42-ce714dc24b94
Robertson, John F
21acd356-2818-4824-b7c7-f5ba62439d15
Smith, Ian E
f2717374-4fc3-4dce-83b3-8f6128ae82cf
Bliss, Judith M
32216b02-f161-4aa5-8a6c-7777c440a458
Dowsett, Mitch
39a1ba62-b1de-478b-bcc6-0a169c415e8e
Cheang, Maggie C U
6074a68e-f537-42c2-aa30-d9d6d1012969
Cutress, Ramsey
68ae4f86-e8cf-411f-a335-cdba51797406

Bergamino, Milana A., López-Knowles, Elena, Morani, Gabriele and Cutress, Ramsey , POETIC investigators (2022) HER2-enriched subtype and novel molecular subgroups drive aromatase inhibitor resistance and an increased risk of relapse in early ER+/HER2+ breast cancer. EBioMedicine, 83, [104205]. (doi:10.1016/j.ebiom.2022.104205).

Record type: Article

Abstract

Background: oestrogen receptor positive/ human epidermal growth factor receptor positive (ER+/HER2+) breast cancers (BCs) are less responsive to endocrine therapy than ER+/HER2- tumours. Mechanisms underpinning the differential behaviour of ER+HER2+ tumours are poorly characterised. Our aim was to identify biomarkers of response to 2 weeks’ presurgical AI treatment in ER+/HER2+ BCs. 

Methods: all available ER+/HER2+ BC baseline tumours (n=342) in the POETIC trial were gene expression profiled using BC360™ (NanoString) covering intrinsic subtypes and 46 key biological signatures. Early response to AI was assessed by changes in Ki67 expression and residual Ki67 at 2 weeks (Ki67 2wk). Time-To-Recurrence (TTR) was estimated using Kaplan-Meier methods and Cox models adjusted for standard clinicopathological variables. New molecular subgroups (MS) were identified using consensus clustering. Findings: HER2-enriched (HER2-E) subtype BCs (44.7% of the total) showed poorer Ki67 response and higher Ki67 2wk (p<0.0001) than non-HER2-E BCs. High expression of ERBB2 expression, homologous recombination deficiency (HRD) and TP53 mutational score were associated with poor response and immune-related signatures with High Ki67 2wk. Five new MS that were associated with differential response to AI were identified. HER2-E had significantly poorer TTR compared to Luminal BCs (HR 2.55, 95% CI 1.14–5.69; p=0.0222). The new MS were independent predictors of TTR, adding significant value beyond intrinsic subtypes. 

Interpretation: our results show HER2-E as a standardised biomarker associated with poor response to AI and worse outcome in ER+/HER2+. HRD, TP53 mutational score and immune-tumour tolerance are predictive biomarkers for poor response to AI. Lastly, novel MS identify additional non-HER2-E tumours not responding to AI with an increased risk of relapse. 

Funding: Cancer Research UK (CRUK/07/015).

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Accepted/In Press date: 22 July 2022
e-pub ahead of print date: 14 September 2022
Additional Information: Funding Information: We would like to thank all POETIC participants and all the staff at the participating sites for their dedication and commitment to the POETIC trial and the collection of good quality samples and data and also Nanostring for their assistance. POETIC is co-sponsored by The Royal Marsden NHS Foundation Trust and The Institute of Cancer Research. POETIC is funded by Cancer Research UK (CRUK/07/015) and coordinated by the Cancer Research UK and Clinical Trials and Statistics Unit at the Institute of Cancer Research (ICR-CTSU). We acknowledge NHS funding to the NIHR Biomedical Research Centre at The Royal Marsden, the ICR and Breast Cancer Now for funding this work as part of Programme Funding to the Breast Cancer Now Toby Robins Research Centre. We also thank Fundación Martin Escudero for Milana Bergamino's fellowship funding and research funding support by NanoString Technologies. Funding Information: We would like to thank all POETIC participants and all the staff at the participating sites for their dedication and commitment to the POETIC trial and the collection of good quality samples and data and also Nanostring for their assistance. POETIC is co-sponsored by The Royal Marsden NHS Foundation Trust and The Institute of Cancer Research. POETIC is funded by Cancer Research UK ( CRUK/07/015 ) and coordinated by the Cancer Research UK and Clinical Trials and Statistics Unit at the Institute of Cancer Research (ICR-CTSU). We acknowledge NHS funding to the NIHR Biomedical Research Centre at The Royal Marsden, the ICR and Breast Cancer Now for funding this work as part of Programme Funding to the Breast Cancer Now Toby Robins Research Centre. We also thank Fundación Martin Escudero for Milana Bergamino's fellowship funding and research funding support by NanoString Technologies.
Keywords: Aromatase Inhibitors, Biomarkers, Tumor/metabolism, Breast Neoplasms/drug therapy, Clinical Trials as Topic, Female, Humans, Ki-67 Antigen/genetics, Neoplasm Recurrence, Local/genetics, Receptor, ErbB-2/genetics, Receptors, Estrogen/genetics, Receptors, Progesterone/metabolism
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Identifiers

Local EPrints ID: 473624
URI: http://eprints.soton.ac.uk/id/eprint/473624
DOI: doi:10.1016/j.ebiom.2022.104205
ISSN: 2352-3964
PURE UUID: 0ede9ef7-0cb0-4a96-8f8f-63cf090665e7

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Date deposited: 25 Jan 2023 17:39
Last modified: 16 Mar 2024 23:45

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Contributors

Author: Milana A. Bergamino
Author: Elena López-Knowles
Author: Gabriele Morani
Author: Holly Tovey
Author: Lucy Kilburn
Author: Eugene F Schuster
Author: Anastasia Alataki
Author: Margaret Hills
Author: Hui Xiao
Author: Chris Holcombe
Author: Anthony Skene
Author: John F Robertson
Author: Ian E Smith
Author: Judith M Bliss
Author: Mitch Dowsett
Author: Maggie C U Cheang
Author: Ramsey Cutress
Corporate Author: POETIC investigators

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