Abstract
The identification of early breast cancer patients who may benefit from adjuvant chemotherapy has evolved to include assessment of clinicopathologic features such as tumor size and nodal status, as well as several gene-expression profiles for ER-positive, HER2-negative cancers. However, these tools do not reliably identify patients at the greatest risk of recurrence. The mutation and copy-number landscape of triple-negative breast cancer (TNBC) subtypes defined by gene expression is also largely unknown, and elucidation of this landscape may shed light on novel therapeutic opportunities. The USO01062 phase III clinical trial of standard chemotherapy (with or without capecitabine) enrolled a cohort of putatively high-risk patients based on clinical features, yet only observed a 5-year disease-free survival event rate of 11.6%. In order to uncover genomic aberrations associated with recurrence, a targeted next-generation sequencing panel was used to compare tumor specimens from patients who had a recurrence event with a matched set who did not. The somatic mutation and copy-number alteration landscapes of high-risk early breast cancer patients were characterized and alterations associated with relapse were identified. Tumor mutational burden was evaluated but was not prognostic in this study, nor did it correlate with PDL1 or CD8 gene expression. However, TNBC subtypes had substantial genomic heterogeneity with a distinct pattern of genomic alterations and putative underlying driver mutations. IMPLICATIONS: The present study uncovers a compendium of genomic alterations with utility to more precisely identify high-risk patients for adjuvant trials of novel therapeutic agents.
Highlights
Breast cancer is a highly heterogeneous disease which for decades has been subtyped and treated based on the IHC staining of three receptors: estrogen receptor (ER), progesterone receptor (PR), and epidermal growth factor receptor 2 (ERBB2, HER2)
A number of elegant studies describing the genomic and transcriptomic profiles of breast cancer and showing the spectrum of mutations and copy-number alterations within IHC- and PAM50-defined subtypes have been published over the past several years [20, 28, 29]
Within triple-negative breast cancer (TNBC), mutations in the tumor suppressor TP53 were the most common genetic alteration, and they occurred throughout the coding region of the gene
Summary
Breast cancer is a highly heterogeneous disease which for decades has been subtyped and treated based on the IHC staining of three receptors: estrogen receptor (ER), progesterone receptor (PR), and epidermal growth factor receptor 2 (ERBB2, HER2). With the seminal paper by Perou and colleagues [1], and follow on work from other groups [2,3,4], the breast cancer community began to appreciate the molecular heterogeneity that exists within breast cancer at the transcriptional level. Gene-expression–based classifiers, such as PAM50 [5], MammaPrint [3], and others, have. Note: Supplementary data for this article are available at Molecular Cancer Research Online (http://mcr.aacrjournals.org/). T.R. Wilson and A.R. Udyavar contributed to this article
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
