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. 2022 Sep:83:104205.
doi: 10.1016/j.ebiom.2022.104205. Epub 2022 Aug 16.

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

Milana A Bergamino  1 , Elena López-Knowles  2 , Gabriele Morani  1 , Holly Tovey  1 , Lucy Kilburn  1 , Eugene F Schuster  2 , Anastasia Alataki  2 , Margaret Hills  3 , Hui Xiao  4 , Chris Holcombe  5 , Anthony Skene  6 , John F Robertson  7 , Ian E Smith  3 , Judith M Bliss  1 , Mitch Dowsett  3 , Maggie C U Cheang  8 ; POETIC investigators
Collaborators, Affiliations

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

Milana A Bergamino et al. EBioMedicine. 2022 Sep.

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 (Ki672wk). 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 Ki672wk (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 Ki672wk. 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).

Keywords: Aromatase inhibitors; Breast cancer; HER2+; HER2-Enriched subtype.

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Conflict of interest statement

Declaration of interests MB reports grants from Fundacion Alonso Martin Escudero and has a patent filed for the novel molecular subgroups identified in this paper. ELK has a patent filed for the novel molecular subgroups identified in this paper. HT and LK report grants from Cancer Research UK, during the conduct of the study. JMB reports grants from Cancer Research UK, during the conduct of the study; grants and non-financial support from AstraZeneca, Merck Sharp & Dohme, Puma Biotechnology, Clovis Oncology, Pfizer, Janssen-Cilag, Novartis, Eli Lilly, and Roche, outside the submitted work. MD receives consulting fees from AstraZeneca, Lilly, Roche, Radius, H3 Biomedicine and G1. He also receives honoraria from Nanostring. M.C.U.C. has a patent for Breast Cancer Classifier: US Patent No. 9,631,239 with royalties paid and receive research funding from NanoString Technologies and Veracyte advisory role. And has a patent filed for the novel molecular subgroups identified in this paper. All other authors declare no competing interests. The information in this manuscript is subject to a pending patent application.

Figures

Figure 1
Figure 1
Ki67 changes from baseline to surgery stratified by intrinsic subtype at baseline within a. Treated and b. Controls. Abbreviations: HER2-E, HER2-Enriched Subtype; LumB, Luminal B subtype; LumA, Luminal A subtype.
Figure 2
Figure 2
Signatures significantly associated with differential response to AI. a. Ordinal regression models in treated patients with Ki67 data (n=227) coloured by FDR for Ki67 response categories and b. Logistic regression models for Ki672wk. Abbreviations: AI, Aromatase inhibitors; logOR, log Odds Ratio; FDR, False discovery rate; HER2-E, HER2-Enriched Subtype; LumB, Luminal B subtype; LumA, Luminal A subtype.
Figure 3
Figure 3
Hierarchical clustering using significant genes from SAM analysis of single gene expression for the different Ki67 endpoints in treated patients. a. Supervised hierarchical clustering of the multiclass SAM analysis for the three Ki67 response categories (GR/IR/PR) (n=226). b. Supervised hierarchical clustering of the two unpaired class SAM analysis (n=226). c. Supervised hierarchical clustering of the genes selected by two class unpaired SAM analysis for Ki672wks categories: High vs Low (n=227): 211 significant genes, 128 associate with low and 83 with high residual Ki67. Abbreviations: HER2-E, HER2-Enriched Subtype; LumB, Luminal B subtype; LumA, Luminal A subtype; Ki672wk, Ki67 at 2 weeks timepoint.
Figure 4
Figure 4
Five new molecular subgroups were identified based on consensus clustering of tumours using expression of 758 genes. Top panel illustrates single gene expression of all genes in treated patients with Ki67 data only (n=226), separated by the 5 novel molecular subgroups. Clusters of genes are annotated according to their functionality. Bottom panel illustrates the expression levels of the 21 multigene signatures, ordered according to the new 5 molecular subgroups. Abbreviations: HER2-E, HER2-Enriched Subtype; LumB, Luminal B subtype; LumA, Luminal A subtype; GR, Good responders; IR, Intermediate responders, PR, Poor Responders; Ki672wk, Ki67 at 2 weeks timepoint, ER, Oestrogen receptor; HRD, Homologous recombination deficiency ECM, extracellular matrix; TIS, Tumour Inflammation Signature; TIGIT, T cell immunoreceptor with Ig and ITIM domain; MHC, Major Histocompatibility complex APM, Antigen Processing Machinery, IFN-gamma, interferon gamma.
Figure 5
Figure 5
Kaplan Meier curves for TTR according to a. all PAM50 intrinsic subtype at baseline; b. HER2-E vs luminals and c. the new molecular subgroups. Abbreviations: TTR: Time to recurrence; HER2-E, HER2-enriched; LumB; Luminal B.
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