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 3320 exons of 182 cancer-related genes plus 37 introns from 14 genes often rearranged in cancer. Point mutations, indels, copy number alterations and select rearrangements were assessed in 74 tumors from 43 patients (36 primary, 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, AKT2. In 33 matched primary and recurrent tumors, 97 of 112 (86.6%) somatic mutations were concordant. Of identified copy number alterations, 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. 40 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 breast cancer patients. Overall there was high concordance between primary and recurrent tumors. Analysis of recurrent tumors prior to treatment may provide additional insights, as both gains and losses of targets are observed.

MultiplexKRASG12/G13 mutation testing of unamplified cell-free DNA from the plasma of patients with advanced cancers using droplet digital polymerase chain reaction

“…Collectively, there is increasing evidence that the mutation analysis results for cfDNA are highly concordant with those for archival tumor tissue for concordantly, but not discordantly, collected samples, which may be explained by tumor biology, including heterogeneity and evolution over time [10,21]. In addition, our KRAS G12/G13 multiplex assay detects seven of the most frequent KRAS G12/G13 mutations in one reaction; in other PCR approaches, this would require seven separate tests.…”

“…Also, mutation status can change over time, and discrepancies between the genomic profiles of primary and metastatic tumors may occur [9][10][11]. Thus, archival FFPE tumor samples, which may be many years old, might not necessarily reflect the pertinent genotype.…”

BRAF Mutation Testing in Cell-Free DNA from the Plasma of Patients with Advanced Cancers Using a Rapid, Automated Molecular Diagnostics System

“…However, the agreement rate is lower if the samples are obtained at different times, which may be explained by tumor heterogeneity and evolution over time. For instance, one such study showed that only 97 of 112 (86.6%) somatic mutations were concordant between 33 matched primary and metastatic breast cancers (9).…”

“…Furthermore, BRAF mutation analysis is not feasible in up to 50% of patients with ErdheimChester histiocytosis (7). Finally, mutation status can change over time, and discrepancies between the genomic profiles of primary and metastatic tumor sites have been reported (8,9). Thus, archival FFPE tumor samples, which may be many years old, might not necessarily reflect the pertinent genotype.…”

Comprehensive Genomic Profiling Identifies Frequent Drug-Sensitive EGFR Exon 19 Deletions in NSCLC not Identified by Prior Molecular Testing

“…For the remaining four cases, CGP was performed on a different specimen, including one case where the samples were collected at the same time, but from different sites, and another case where hotspot testing was performed on a sample with low cellularity and reported a negative result, prompting the treating physician to request that another sample be collected and submitted for CGP. In general, oncogenic drivers have been demonstrated to be highly concordant in primary and metastatic biopsies across a variety of tumor types (14)(15)(16)(17). Explanation of the discordance between hotspot results and CGP observed here awaits further analysis.…”