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

Abstract

Although 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. SCNAs 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 <i>MKI67</i> gene [Ki-67]) and 28 good responders (GdRs, greater than 75% reduction in Ki-67). Exome sequencing was available for 72 pairs of samples. Genomic instability correlated with Ki-67 expression at both baseline (<i>P</i> < .001) and surgery (<i>P</i> < .001) and was higher in PrRs (<i>P</i> = .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 <i>TP53.</i> Nine of 28 PrRs had loss of wild-type <i>TP53</i> as a result of mutations and loss of heterozygosity compared with three of 28 GdRs. In PrRs, somatic alterations of <i>TP53</i> were associated with higher genomic instability, higher baseline Ki-67, and greater resistance to AI treatment compared with wild-type <i>TP53</i>. We 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.