Abstract
Aromatase inhibitor (AI) treatment is the standard of care for postmenopausal women with primary estrogen receptor-positive breast cancer. The impact of duration of neoadjuvant endocrine therapy (NET) on molecular characteristics is still unknown. We evaluated and compared changes of gene expression profiles under short-term (2-week) versus longer-term neoadjuvant AIs. Global gene expression profiles from the PeriOperative Endocrine Therapy for Individualised Care (POETIC) trial (137 received 2 weeks of AIs and 47 received no treatment) and targeted gene expression from 80 patients with breast cancer treated with NET for more than 1 month (NeoAI) were assessed. Intrinsic subtyping, module scores covering different cancer pathways and immune-related genes were calculated for pretreated and posttreated tumors. The differences in intrinsic subtypes after NET were comparable between the two cohorts, with most Luminal B (90.0% in the POETIC trial and 76.3% in NeoAI) and 50.0% of HER2 enriched at baseline reclassified as Luminal A or normal-like after NET. Downregulation of proliferative-related pathways was observed after 2 weeks of AIs. However, more changes in genes from cancer-signaling pathways such as MAPK and PI3K/AKT/mTOR and immune response/immune-checkpoint components that were associated with AI-resistant tumors and differential outcome were observed in the NeoAI study. Tumor transcriptional profiles undergo bigger changes in response to longer NET. Changes in HER2-enriched and Luminal B subtypes are similar between the two cohorts, thus AI-sensitive intrinsic subtype tumors associated with good survival might be identified after 2 weeks of AI. The changes of immune-checkpoint component expression in early AI resistance and its impact on survival outcome warrants careful investigation in clinical trials.
Highlights
Breast cancer (BC) is molecularly and clinically heterogeneous, with approximately 60-80% of cases being estrogen receptor positive (ER+)
The differences in intrinsic subtypes after neoadjuvant endocrine therapy (NET) were comparable between the two cohorts, with most Luminal B (90.0% in POETIC and 76.3% in NeoAI) and 50.0% of HER2enriched at baseline re-classified as Luminal A or Normal-like after NET
More changes in genes from cancer-signaling pathways such as MAPK and PI3K/AKT/mTOR and immune response/immune-checkpoint components that were associated with Aromatase inhibitors (AI) resistant tumours and differential outcome were observed in the NeoAI study
Summary
Breast cancer (BC) is molecularly and clinically heterogeneous, with approximately 60-80% of cases being estrogen receptor positive (ER+). The elucidation of the molecular intrinsic subtypes has led to the categorisation of BC tumours into clinically relevant but molecular distinct subgroups that can be optimally defined by the 50-genes based PAM50 classifier [8,9,10]. These molecular subtypes are associated with different incidence and racial disparity, response to treatment and prognosis [8]. The impact of short- and long-term neoadjuvant AI therapy on molecular changes, including intrinsic subtypes and signalling pathways was comprehensively evaluated. We evaluated and compared changes of gene expression profiles under short-term (2-week) versus longer-term neoadjuvant AI
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