Abstract PD5-05: Genomic instability and poor antiproliferative response to aromatase inhibitor treatment: A POETIC study
Authors: Schuster EF , Gellert P , Segal CV , López-Knowles E , Buus R , Morden J , Robertson J , Bliss J , Smith I , Dowsett M ,   POETIC Trial Management Group and Trialists P
Published: February 2018

Background:

More than 20% of early-stage patients with estrogen positive (ER+) disease relapse. Higher levels of the proliferation marker Ki67, and lack of reduction of Ki67 in response to AI indicate poorer prognosis. Somatic mutations have been the focus of research in treatment resistance. However, recurrent somatic copy number alterations (SCNAs) are more common and affect more genes in primary breast cancer (BC) than somatic mutations. Previous studies have suggested an increased risk of recurrence for patients with high genomic instability and for patients with loss of heterozygosity (LOH) at the TP53 locus, but it is unknown if these SCNA events impact response to AI treatment. In addition, LOH and mutations at the TP53 locus had a higher risk of recurrence than LOH or mutations at TP53 alone. We hypothesised that genomic instability and SCNAs at particular loci would be increased in early BC patients with high baseline Ki67, and particularly in patients with high Ki67 despite pre-operative AI therapy.

Methods:

In a substudy of POETIC (UK-wide, phase III, randomised trial with 4483 women testing perioperative AI in postmenopausal women with early BC), SNParray technology was used to determine SCNAs in baseline and surgical tumour core-cuts and blood from 76 patients (59 AI-treated, 17 controls). Proliferation rate was estimated as percentage (%) of cancer cells staining for Ki67 by IHC. Poor AI responders (PR, &lt;60% reduction in Ki67 between baseline and surgery, n=31) and good AI responders (GR, &gt; 75% reduction in Ki67, n=28) were selected from POETIC samples. Mutation data from exome sequencing was available for tumours from 75 of the patients.

Results:

The fraction of the genome with SCNAs correlated with Ki67 expression in both baseline and surgical samples (baseline Spearman rho=0.5, p &lt; 10-5; surgical Spearman rho=0.44, p &lt; 10-3). In paired baseline vs surgical samples, 24% of samples showed discordance in SCNAs that covered &gt; 10% of the genome. The samples showing the highest discordance were from PRs.

The fraction of the genome with LOH was greater in PR (median PR 20%, GR 10%, p = .065), and the best SCNA to predict the fraction of the genome altered in a sample were segments with LOH at Chr17p13.3 (adjusted p &lt; .001, logistic regression). There was a higher percentage of patients with LOH at Chr17p13.3 that contains the TP53 gene in the PR compared to GR group (PR 71%, GR 39%, p = .029), and integration of previously generated mutation data with SCNA showed that 9 out of 31 PRs have mutations and LOH at the TP53 locus compared to 3 out of 28 GRs (p = 0.16).

Conclusions:

There is discordance between the observed SCNAs in paired samples with high genomic instability and multiple biopsies may be needed to confidently assess all SCNAs. However, LOH at Chr17p13.3 is a biomarker for genomic instability and frequency of LOH is significantly greater in patients that show a poor response to AI treatment. Finally, high genomic instability is associated with high proliferation rates at baseline and surgery after 2 weeks of AI treatment suggesting de novo resistance in tumours with high instability that may lead to a higher rate of recurrence seen in these patients.

Citation Format: Schuster EF, Gellert P, Segal CV, López-Knowles E, Buus R, Morden J, Robertson J, Bliss J, Smith I, Dowsett M, POETIC Trial Management Group and Trialists P. Genomic instability and poor antiproliferative response to aromatase inhibitor treatment: A POETIC study [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr PD5-05.