Abstract PD15-02: HER2-enriched subtype and novel molecular subgroups drive aromatase inhibitor resistance and an increased risk of relapse in early ER+/HER2+ breast cancer
Authors: Sirvén Milana A Bergamino , López-Knowles Elena , Morani Gabriele , Tovey Holly , Kilburn Lucy , Holcombe Chris , Skene Anthony , Smith Ian , Robertson John , Schuster Gene , Bliss Judith M , Dowsett Mitch , Cheang Maggie CU ,   POETIC investigators
Published: March 2022

Abstract
Background: Approximately 10% of estrogen receptor positive (ER+) early breast cancers (EBC) are human epidermal growth factor positive/overexpressed (HER2+). Resistance to aromatase inhibitors (AIs) is poorly understood among ER+HER2+ BC. We aimed to identify biomarkers of response and resistance using the HER2+ tumours in the POETIC trial. Methods: POETIC was a phase III trial of post-menopausal women with ER+ EBC randomized 2:1 to 2-weeks of peri-surgical AI vs control, followed by standard-of-care. Baseline formalin-fixed paraffin-embedded samples from 342 ER+HER2+ BC (237 treated/105 controls) were gene expression profiled using Breast cancer 360™ panel (NanoString) covering intrinsic subtypes and 40 key biological signatures. New molecular subgroups were identified using consensus clustering (CC).Proliferation rate was estimated as percentage of cancer-cells staining for Ki67. Ki67 response was defined by percentage-changes from baseline to surgery: poor (PR; reduction &lt;50%), intermediate (IR; 50-75%) and good (GR; &gt;75%). Residual Ki67 at 2 weeks timepoint (Ki672w) was defined as High (H) (≥ 10%) vs Low (L) (&lt;10%). Association of molecular features with Ki67 response was assessed using logistic regression models and with time to recurrence (TTR) using multivariable Cox regression models adjusted for post-surgery clinicopathological variables: grade, tumour size, nodal status and age. Results: Ki672w was measured for all treated samples (n = 227, 48% H, 52% L) and a fraction of controls (n = 50, 96% H, 4% L). At baseline, 45% of tumours were HER2-enriched (HER2-E), 53% Luminal A/B and 2% Basal-Like. HER2-E associated with high Ki672W (84% H, 16% L) compared to non-HER2-E (29% H, 71% L, p&lt;0.001). Amongst the 40 BC360 signatures, 9 were significantly associated with Ki67 response (Table).
High expression of endocrine-related and apoptosis signatures associated with GR while HRD and TP53 with PR. These features were also related to Ki672W, with additional signatures involved in immune-checkpoint component and immune-enrichment (IM) (IDO1, PD-L1, IFN-gamma and T-reg) associated with high Ki672W.. Using CC, 4 molecular subgroups predicting differential response to AI were identified. Cluster (C) 1 was characterized by overexpression of IM features and low ER signaling (42%); C2 low IM but highest ERBB2 expression (15%); C3 ESR1 high and PgR low (4%) and C4 high endocrine signaling and lowest ERBB2 expression (39%). Distribution of Intrinsic subtypes varied across these molecular subgroups with the majority of C1 being HER2-E (62%) and Luminal B (27%); C2 HER2-E (74%); C3 Luminal B (64%) and C4 Luminal B (55%) and Luminal A (30%). HER2-E had significantly poorer TTR (HR 2.14; 95%CI1.11-4.17; p=0.0224) compared to Luminal tumours, remaining significant (HR 2.55, 95%CI1.14-5.69; p=0.0222) in the multivariable analysis. C2 (HR 4.67, 95%CI 1.90-11.51; p&lt;0.001) and C4 (HR 2.42, 95%CI1.05-4.5.58; p=0.0385) were independent predictors of shorter TTR compared to C1, adding significant value beyond intrinsic subtypes (Likelihood ratio test, p=0.00429). Conclusions: Our results confirm that HER2-E, TP53 mutation, HRD and IM features are the main components driving poor early response to AI in ER+/HER2+ EBC. Novel molecular subgroups identify additional non-HER-E tumours not responding to AI with an increased risk of relapse. The appropriate additional treatment warrants further investigation.
List of significant gene expression signatures associated with response as defined by reduction of Ki67. Odds ratio (OR) were determined by ordinal logistic regression analyses. OR: &lt;1 indicating associated with good response and &gt; 1.0 associated with worse response.Odds Ratiop-valuep-adjusted (False Discovery Rate)ESR10.65&lt; 0.001&lt; 0.001Estrogen Receptor Signaling0.44&lt; 0.001&lt; 0.001ERBB21.52&lt; 0.001&lt; 0.001TP53 mutant signature2.65&lt; 0.001&lt; 0.001FOXA10.42&lt; 0.001&lt; 0.001Apoptosis0.26&lt; 0.0010.00228Homologous Recombination Deficiency (HRD)2.33&lt; 0.0010.00349PgR0.820.001480.00737Hypoxia2.180.001660.00737
Citation Format: Milana A Bergamino Sirvén, Elena López-Knowles, Gabriele Morani, Holly Tovey, Lucy Kilburn, Chris Holcombe, Anthony Skene, Ian Smith, John Robertson, Gene Schuster, Judith M Bliss, Mitch Dowsett, Maggie CU Cheang, POETIC investigators. HER2-enriched subtype and novel molecular subgroups drive aromatase inhibitor resistance and an increased risk of relapse in early ER+/HER2+ breast cancer [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr PD15-02.