Genomic Instability and TP53 Genomic Alterations Associate With Poor Antiproliferative Response and Intrinsic Resistance to Aromatase Inhibitor Treatment.

Eugene F Schuster,Pascal Gellert,Elena López-Knowles,Richard Buus,Maggie Chon U Cheang,James Morden,John Robertson,Mitch Dowsett,Corrinne V Segal,Ian Smith,Judith M Bliss

doi:10.1200/po.18.00286

Abstract

PURPOSEAlthough aromatase inhibitor (AI) treatment is effective in estrogen receptor–positive postmenopausal breast cancer, resistance is common and incompletely explained. Genomic instability, as measured by somatic copy number alterations (SCNAs), is important in breast cancer development and prognosis. SCNAs to specific genes may drive intrinsic resistance, or high genomic instability may drive tumor heterogeneity, which allows differential response across tumors and surviving cells to evolve resistance to treatment rapidly. We therefore evaluated the relationship between SCNAs and intrinsic resistance to treatment as measured by a poor antiproliferative response.PATIENTS AND METHODSSCNAs were determined by single nucleotide polymorphism array in baseline and surgery core-cuts from 73 postmenopausal patients randomly assigned to receive 2 weeks of preoperative AI or no AI in the Perioperative Endocrine Therapy—Individualizing Care (POETIC) trial. Fifty-six samples from the AI group included 28 poor responders (PrRs, less than 60% reduction in protein encoded by the MKI67 gene [Ki-67]) and 28 good responders (GdRs, greater than 75% reduction in Ki-67). Exome sequencing was available for 72 pairs of samples.RESULTSGenomic instability correlated with Ki-67 expression at both baseline (P < .001) and surgery (P < .001) and was higher in PrRs (P = .048). The SCNA with the largest difference between GdRs and PrRs was loss of heterozygosity observed at 17p (false discovery rate, 0.08), which includes TP53. Nine of 28 PrRs had loss of wild-type TP53 as a result of mutations and loss of heterozygosity compared with three of 28 GdRs. In PrRs, somatic alterations of TP53 were associated with higher genomic instability, higher baseline Ki-67, and greater resistance to AI treatment compared with wild-type TP53.CONCLUSIONWe observed that primary tumors with high genomic instability have an intrinsic resistance to AI treatment and do not require additional evolution to develop resistance to estrogen deprivation therapy.

Highlights

Estrogen deprivation is the major treatment strategy for hormone-dependent breast cancer (BC) and typically involves agents that inhibit aromatase, the enzyme that catalyzes the conversion of androgens to estrogens
The Perioperative Endocrine Therapy—Individualizing Care (POETIC) phase III trial with 2 weeks of perioperative aromatase inhibitor (AI) therapy offers the opportunity to identify mechanisms and biomarkers of intrinsic AI resistance, and in the POETIC trial, up to 20% of tumors showed resistance to AI treatment after just 2 weeks of treatment
The results show that high genomic instability is associated with AI resistance, and detection of copy number alterations and mutations in TP53 are predictive of high genomic instability

Summary

Introduction

Estrogen deprivation is the major treatment strategy for hormone-dependent breast cancer (BC) and typically involves agents that inhibit aromatase, the enzyme that catalyzes the conversion of androgens to estrogens. Despite near-complete suppression of circulating estrogen levels by aromatase inhibitor (AI) treatment, acquired and de novo resistance to AI is common.[1] Few pretreatment biomarkers exist for AI resistance, and mechanisms of resistance are incompletely understood.[2].

Methods

Results

Conclusion