Impact of mutational profiles on response of primary oestrogen receptor-positive breast cancers to oestrogen deprivation

Abstract

Pre-surgical studies allow study of the relationship between mutations and response of oestrogen receptor-positive (ER+) breast cancer to aromatase inhibitors (AIs) but have been limited to small biopsies. Here in phase I of this study, we perform exome sequencing on baseline, surgical core-cuts and blood from 60 patients (40 AI treated, 20 controls). In poor responders (based on Ki67 change), we find significantly more somatic mutations than good responders. Subclones exclusive to baseline or surgical cores occur in ∼30% of tumours. In phase II, we combine targeted sequencing on another 28 treated patients with phase I. We find six genes frequently mutated: PIK3CA, TP53, CDH1, MLL3, ABCA13 and FLG with 71% concordance between paired cores. TP53 mutations are associated with poor response. We conclude that multiple biopsies are essential for confident mutational profiling of ER+ breast cancer and TP53 mutations are associated with resistance to oestrogen deprivation therapy.

NeoPalAna: Neoadjuvant Palbociclib, a Cyclin-Dependent Kinase 4/6 Inhibitor, and Anastrozole for Clinical Stage 2 or 3 Estrogen Receptor–Positive Breast Cancer

“…Two tumors sensitive to palbociclib by Ki67 (>2.7% at C1D1, ≤2.7% at C1D15) were found to have missense RB1 mutations on baseline biopsies, PD131 ( RB1 p.A562P and p.S576*) and PD203 ( RB1 p.I532N – absent at subsequent time points). Although the sequencing depth were relatively high (92-400X), in the setting of low VAF, explanations for the disappearance of the RB1 p.I532N at subsequent time points include intra-tumoral heterogeneity in potentially spatially separated biopsies (34), clonal evolution in response to treatment (22), or sequencing artifact.…”

The impact of cigarette smoke exposure, and COPD or asthma status on ABC transporter gene expression in human airway epithelial cells

“…ABCA13 is an intriguing candidate as the expression levels are very high relative to other ABC family members, and there are no reports of endogenous or exogenous substrates, expression patterns in epithelium, or associations with respiratory mucosal immunology. Reports show associations between ABCA13 expression and cancers [35][36][37] , while ABCA13 variants are associated with mental health abnormalities 38,39 , although no mechanisms have been defined for either of these observations. Other ABCA family members are involved in lipid transport and dysregulation of their pathways can result in lung inflammation 40 .…”

Neoadjuvant Trials in ER+ Breast Cancer: A Tool for Acceleration of Drug Development and Discovery

“…Despite the relatively short treatment, several mutations were selected for or enriched after therapy, including two activating ESR1 mutations. In a second study, Gellert et al (59) performed whole exome sequencing on baseline, surgical core-cuts and blood from 40 patients treated with an AI for 2 weeks. In resistant tumors where the Ki67 remained high, there were more somatic mutations than in good responders.…”