Concordance of genomic alterations between primary and recurrent breast cancer

Abstract

There is growing interest in delivering genomically informed cancer therapy. Our aim was to determine the concordance of genomic alterations between primary and recurrent breast cancer. Targeted next-generation sequencing was performed on formalin-fixed paraffin-embedded (FFPE) samples, profiling 3,320 exons of 182 cancer-related genes plus 37 introns from 14 genes often rearranged in cancer. Point mutations, indels, copy-number alterations (CNA), and select rearrangements were assessed in 74 tumors from 43 patients (36 primary and 38 recurrence/metastases). Alterations potentially targetable with established or investigational therapeutics were considered "actionable." Alterations were detected in 55 genes (mean 3.95 alterations/sample, range 1-12), including mutations in PIK3CA, TP53, ARID1A, PTEN, AKT1, NF1, FBXW7, and FGFR3 and amplifications in MCL1, CCND1, FGFR1, MYC, IGF1R, MDM2, MDM4, AKT3, CDK4, and AKT2. In 33 matched primary and recurrent tumors, 97 of 112 (86.6%) somatic mutations were concordant. Of identified CNAs, 136 of 159 (85.5%) were concordant: 37 (23.3%) were concordant, but below the reporting threshold in one of the matched samples, and 23 (14.5%) discordant. There was an increased frequency of CDK4/MDM2 amplifications in recurrences, as well as gains and losses of other actionable alterations. Forty of 43 (93%) patients had actionable alterations that could inform targeted treatment options. In conclusion, deep genomic profiling of cancer-related genes reveals potentially actionable alterations in most patients with breast cancer. Overall there was high concordance between primary and recurrent tumors. Analysis of recurrent tumors before treatment may provide additional insights, as both gains and losses of targets are observed.

Figure 1. Genomic alterations in primary (A) and metastatic or recurrent (B) tumors

Each column represents a single tumor sample. The total number of alterations in a sample is indicated at the bottom of each column. Each row represents an individual gene. Bar graphs on the right summarize the types of alterations seen for each gene.

Figure 2. Comparison of Genomic Alterations in Primary or Metastatic or Recurrent Samples

A. Unsupervised clustering of primary and metastatic or recurrent samples. B. Most common genomic alterations (mutations and copy number changes) in primary and metastatic tumors in our series.

Figure 3. Discordant genomic alterations

Mutations are represented in blue, copy number changes in red. P, alterations found in primary tumor samples but not in matched recurrent/metastatic tumor samples. M, alterations found in recurrent/metastatic tumor samples but not in matched primary tumor samples.